We propose to examine responses of hippocampal neurons to iontophoresis of putative excitatory amino-acid neurotransmitters. The in vitro hippocampal-slice preparation will be used. Intracellular recording will be combined with iontophoresis of transmitter agents to known portions of the dendritic tree and with manipulation of the extracellular microenvironment. Voltage-clamping will be performed, using a single-electrode, time-sharing system. The objectives of this research proposal are to determine the mechanism whereby excitatory amino acids (including glutamate, aspartate, kainic acid, homocysteic acid, and N-methyl-DL-aspartic acid) excite hippocampal neurons and to study the conductance changes and ionic dependencies of their actions. We wish to determine if the various amino acids exert their effects via a single receptor or if distinct receptor populations are present. This will be achieved by iontophoresing the above-named compounds and bath-applying known concentrations of antagonist agents. The kinetics of the transmitter-receptor complex will be studied in terms of its stoichiometry and voltage dependence. This will be accomplished, respectively, by quantitative analysis of dose-response curves and by noise analysis of membrane current fluctuations. This proposal will address problems of fundamental importance in the areas of neurophysiology, neuropharmacology, and neurology. The results will advance our understanding of the action of excitatory amino acids at the cellular level, which will be of benefit in unraveling higher order processes, such as synaptic plasticity and learning, and in increasing our knowledge of disease processes, such as epilepsy and Huntington's chorea.